Activité cérébrale volontaire chez les patients récupérant du coma: Une approche multi-modale

Après un coma, certains patients restent de manière prolongée dans un état végétatif/ syndrome d'éveil non répondant (VS/UWS, éveil sans conscience), un état de conscience minimale (MCS, éveil et fluctuation de la conscience) [1] récemment, sous-catégorisé en état de conscience minimale moins (MCS-, présentant un comportement orienté non-reflexe) et état de conscience minimale plus (MCS+, montrant une réponse à la commande)] ou une émergence de l’étatde conscience minimale (EMCS, utilisation fonctionnelle d’objet et/oucommunication fonctionnelle) avant de récupérer ou non leur état de conscienceinitiale. Certains patients peuvent également rester en VS/UWS ou en MCSpendant des années. Par ailleurs, une minorité de ces patients se réveillentconscients, mais paralysés et sans voix (i.e. locked-in syndrome, LIS), et sont catégorisés à tort en VS/UWS.L’évaluation comportementale est l’outil principal pour établir un diagnostic mais la pratique clinique démontre qu’il reste encore difficile de détecter des signes de conscience au chevet des patients, avec un taux d’erreur diagnostique d’environ 40%. Il est dès lors nécessaire d’utiliser d’autres méthodes plus objectives afin de réduire ce taux d’erreur, comme les techniques de neuroimagerie,d’électrophysiologie ou d’électromyographie (EMG) qui permettent de détecter une réponse mentale à la commande ou des micromouvements volontaires qui ne peuvent être détectés visuellement, ainsi que les interfacescerveau-ordinateur (BCIs) qui permettent de détecter et d’établir une communication potentielle chez les patients avec lésions cérébrales sévères. L’objectif principal de cette thèse est de développer et de valider des outils objectifs et sensibles qui permettront d’évaluer une cognition, même basique, etde détecter des signes de conscience, même subtils, chez des patientssévèrement cérébro-lésés. Dans ce contexte, nous avons effectué quatre études, deux études EMG et deux études BCI. Noter que les méthodesélectrophysiologiques sont plus faciles à utiliser et moins chères que les méthodes de neuro-imagerie. Pour cette raison, nous avons focalisé notre travail sur les méthodes électrophysiologiques. L'objectif de la première étude est donc de valider l'utilisation de l’EMG pourdétecter des réponses à la commande chez les patients en VS / UWS ou MCS.Trente-huit patients ont été inclus dans cette étude (23 traumatiques, 25 patients > 1 an après lésions cérébrales, 10 VS / UWS, 8 MCS- et 20 MCS+). Dix-huit contrôles appariés selon l'âge ont aussi participé à l'expérience. Le paradigme estcomposé de plusieurs commandes présentées dans un ordre aléatoire: « serrer les mains », « bouger les jambes » et « serrer les dents » ainsi qu’une phrase contrôle « Il fait beau ». Chaque stimulation auditive a été répétée quatre fois dans un seul bloc de 30 secondes. Les analyses post-hoc avec correction de Bonferroni ont révélé que les activités EMG étaient plus élevées pour la commande cible, suggérant une réponse volontaire à la commande, chez un patient diagnostiqué VS / UWS permanent (ainsi que chez trois patients MCS+). Afin de confirmer l'intérêt de l'EMG lors de la détection de réponses volontaireschez les patients ayant des lésions cérébrales graves, nous avons effectué une deuxième étude EMG en développant une nouvelle méthode. Quarante patients ont été inclus dans cette étude (20 traumatiques, 24 patients > 1 an après lésions cérébrales, 15 VS / UWS, 7 MCS-, 13 MCS+, 3 EMCS et 2 LIS). Nous avons inclus 20 volontaires sains sans antécédents de troubles neurologiques et appariés à l'âge des patients. Nous avons prolongé le temps de l’expérience où chaque stimulation auditive a été répétée cinq fois dans un seul bloc de 10 minutes; nous avions trois blocs dans cette expérience (donc, 15 présentations dela commande). Nous avons développé une méthode de « décodage simple » del'activité musculaire résiduelle, permettant d’utiliser l’EMG pour communiquer en direct. Les résultats ont montré une réponse à la commande chez 15 VS / UWS, 2/8 MCS- 14/14 MCS+, 3/3 EMCS et 2/2 LIS.Nous avons également effectué deux études sur l’utilisation des BCIs afin de détecter un contrôle volontaire qui permette d’évaluer objectivement la réponse à la commande chez des patients LIS et des patients avec troubles de la conscience. Dans la première étude BCI, nous avons utilisé une plateforme afin d’évaluer la communication en direct. Douze volontaires sains et six LIS ont étéinclus dans cette étude. Il y avait deux parties dans cette expérience : une partie d’entraînement hors-ligne pour détecter la réponse à la commande et l’autre partie pour la communication fonctionnelle en direct. Huit des douze volontairessains et un des quatre patients LIS ont présenté une communicationfonctionnelle. L’évaluation des performances durant la première partied’entraînement hors-ligne a permis de détecter une réponse à la commande chez deux des six patients LIS, tandis que la deuxième partie a permis de détecter une communication fonctionnelle chez un patient LIS. Cet outil permettrait donc nonseulement de détecter une réponse à la commande hors-ligne mais aussi d’établir une communication en direct avec les patients conscients mais paralysés.Dans la deuxième étude BCI, nous avons utilisé l’électroencephalographie et,plus exactement, les potentiels évoqués visuels en régime permanent (steadystate visual evoked potential; SSVEP) avec modulation de l’attention durant une tâche active. Cette modulation volontaire de l’attention a été évaluée à l’aide de l’entropie spectrale chez les patients ayant des troubles de la conscience. Pour détecter une réponse à la commande, nous avons inclus dans cette étude vingt volontaires sains, six LIS et trente patients avec troubles de la conscience: seize VS/UWS, neuf MCS-, trois MCS+, et deux EMCS. Une réponse a été observée chez l’ensemble des patients LIS (94%) et EMCS (71%), chez deux patients MCS+ (59%), tandis que l’ensemble des patients VS/UWS et MCS- ont présenté des performances au niveau de la chance. Le faible taux de faux négatifs (9%) et l’absence de faux positifs (0%) suggèrent la pertinence de ce nouvel outil diagnostique qui offre de meilleures performances que les BCIs proposées précédemment dans la littérature (taux de faux négatifs compris entre25 et 100%)

Toward an attention-based diagnostic tool for patients with locked-in syndrome

Electroencephalography (EEG) has been proposed as a supplemental tool for reducing clinical misdiagnosis in severely brain-injured populations helping to distinguish conscious from unconscious patients. We studied the use of spectral entropy as a measure of focal attention in order to develop a motor-independent, portable, and objective diagnostic tool for patients with locked-in syndrome (LIS), answering the issues of accuracy and training requirement. Data from 20 healthy volunteers, 6 LIS patients, and 10 patients with a vegetative state/unresponsive wakefulness syndrome (VS/UWS) were included. Spectral entropy was computed during a gaze-independent 2-class (attention vs rest) paradigm, and compared with EEG rhythms (delta, theta, alpha, and beta) classification. Spectral entropy classification during the attention-rest paradigm showed 93% and 91% accuracy in healthy volunteers and LIS patients respectively. VS/UWS patients were at chance level. EEG rhythms classification reached a lower accuracy than spectral entropy. Resting-state EEG spectral entropy could not distinguish individual VS/UWS patients from LIS patients. The present study provides evidence that an EEG-based measure of attention could detect command-following in patients with severe motor disabilities. The entropy system could detect a response to command in all healthy subjects and LIS patients, while none of the VS/UWS patients showed a response to command using this system

Global burden and strength of evidence for 88 risk factors in 204 countries and 811 subnational locations, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

Background: Understanding the health consequences associated with exposure to risk factors is necessary to inform public health policy and practice. To systematically quantify the contributions of risk factor exposures to specific health outcomes, the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 aims to provide comprehensive estimates of exposure levels, relative health risks, and attributable burden of disease for 88 risk factors in 204 countries and territories and 811 subnational locations, from 1990 to 2021. Methods: The GBD 2021 risk factor analysis used data from 54 561 total distinct sources to produce epidemiological estimates for 88 risk factors and their associated health outcomes for a total of 631 risk–outcome pairs. Pairs were included on the basis of data-driven determination of a risk–outcome association. Age-sex-location-year-specific estimates were generated at global, regional, and national levels. Our approach followed the comparative risk assessment framework predicated on a causal web of hierarchically organised, potentially combinative, modifiable risks. Relative risks (RRs) of a given outcome occurring as a function of risk factor exposure were estimated separately for each risk–outcome pair, and summary exposure values (SEVs), representing risk-weighted exposure prevalence, and theoretical minimum risk exposure levels (TMRELs) were estimated for each risk factor. These estimates were used to calculate the population attributable fraction (PAF; ie, the proportional change in health risk that would occur if exposure to a risk factor were reduced to the TMREL). The product of PAFs and disease burden associated with a given outcome, measured in disability-adjusted life-years (DALYs), yielded measures of attributable burden (ie, the proportion of total disease burden attributable to a particular risk factor or combination of risk factors). Adjustments for mediation were applied to account for relationships involving risk factors that act indirectly on outcomes via intermediate risks. Attributable burden estimates were stratified by Socio-demographic Index (SDI) quintile and presented as counts, age-standardised rates, and rankings. To complement estimates of RR and attributable burden, newly developed burden of proof risk function (BPRF) methods were applied to yield supplementary, conservative interpretations of risk–outcome associations based on the consistency of underlying evidence, accounting for unexplained heterogeneity between input data from different studies. Estimates reported represent the mean value across 500 draws from the estimate's distribution, with 95% uncertainty intervals (UIs) calculated as the 2·5th and 97·5th percentile values across the draws. Findings: Among the specific risk factors analysed for this study, particulate matter air pollution was the leading contributor to the global disease burden in 2021, contributing 8·0% (95% UI 6·7–9·4) of total DALYs, followed by high systolic blood pressure (SBP; 7·8% [6·4–9·2]), smoking (5·7% [4·7–6·8]), low birthweight and short gestation (5·6% [4·8–6·3]), and high fasting plasma glucose (FPG; 5·4% [4·8–6·0]). For younger demographics (ie, those aged 0–4 years and 5–14 years), risks such as low birthweight and short gestation and unsafe water, sanitation, and handwashing (WaSH) were among the leading risk factors, while for older age groups, metabolic risks such as high SBP, high body-mass index (BMI), high FPG, and high LDL cholesterol had a greater impact. From 2000 to 2021, there was an observable shift in global health challenges, marked by a decline in the number of all-age DALYs broadly attributable to behavioural risks (decrease of 20·7% [13·9–27·7]) and environmental and occupational risks (decrease of 22·0% [15·5–28·8]), coupled with a 49·4% (42·3–56·9) increase in DALYs attributable to metabolic risks, all reflecting ageing populations and changing lifestyles on a global scale. Age-standardised global DALY rates attributable to high BMI and high FPG rose considerably (15·7% [9·9–21·7] for high BMI and 7·9% [3·3–12·9] for high FPG) over this period, with exposure to these risks increasing annually at rates of 1·8% (1·6–1·9) for high BMI and 1·3% (1·1–1·5) for high FPG. By contrast, the global risk-attributable burden and exposure to many other risk factors declined, notably for risks such as child growth failure and unsafe water source, with age-standardised attributable DALYs decreasing by 71·5% (64·4–78·8) for child growth failure and 66·3% (60·2–72·0) for unsafe water source. We separated risk factors into three groups according to trajectory over time: those with a decreasing attributable burden, due largely to declining risk exposure (eg, diet high in trans-fat and household air pollution) but also to proportionally smaller child and youth populations (eg, child and maternal malnutrition); those for which the burden increased moderately in spite of declining risk exposure, due largely to population ageing (eg, smoking); and those for which the burden increased considerably due to both increasing risk exposure and population ageing (eg, ambient particulate matter air pollution, high BMI, high FPG, and high SBP). Interpretation: Substantial progress has been made in reducing the global disease burden attributable to a range of risk factors, particularly those related to maternal and child health, WaSH, and household air pollution. Maintaining efforts to minimise the impact of these risk factors, especially in low SDI locations, is necessary to sustain progress. Successes in moderating the smoking-related burden by reducing risk exposure highlight the need to advance policies that reduce exposure to other leading risk factors such as ambient particulate matter air pollution and high SBP. Troubling increases in high FPG, high BMI, and other risk factors related to obesity and metabolic syndrome indicate an urgent need to identify and implement interventions

Coma and related disorders

Disorders of consciousness represent a major challenge in clinical practice. The last decade of neuroscience research brought new insights about brain function and neural correlates of these pathological states of consciousness. Although behavioural evaluation still remains the gold standard, conscious behaviours are too often missed, leading to unwanted grey zones between conscious and unconscious patients. In order to increase the chances of detecting the signs of consciousness, scientists now focus on the development and validation of neuroimaging and electrophysiological paradigms in noncommunicative patients. Recent insights in this field also raise new questions of medical ethics. Indeed, for conscious patients, legal questions will occur about treatment plans, rehabilitation and communication strategies while for the unconscious patients, end-of-life decisions will take place after the patients’ condition is stated as “permanent” or “irreversible”

Volitional electromyographic responses in disorders of consciousness

The aim of the study was to validate the use of electromyography (EMG) for detecting responses to command in patients in vegetative state/unresponsive wakefulness syndrome (VS/UWS) or in minimally conscious state (MCS). Methods: Thirty-eight patients were included in the study (23 traumatic, 25 patients >1 year post-onset), 10 diagnosed as being in VS/UWS, eight in MCS- (no response to command) and 20 in MCS+ (response to command). Eighteen age-matched controls participated in the experiment. The paradigm consisted of three commands (i.e. 'Move your hands', 'Move your legs' and 'Clench your teeth') and one control sentence (i.e. 'It is a sunny day') presented in random order. Each auditory stimulus was repeated 4-times within one block with a stimulus-onset asynchrony of 30 seconds. Results: Post-hoc analyses with Bonferroni correction revealed that EMG activity was higher solely for the target command in one patient in permanent VS/UWS and in three patients in MCS+. Conclusion: The use of EMG could help clinicians to detect conscious patients who do not show any volitional response during standard behavioural assessments. However, further investigations should determine the sensitivity of EMG as compared to neuroimaging and electrophysiological assessments

Electromyographic decoding of response to command in disorders of consciousness

Objective: To propose a new methodology based on single-trial analysis for detecting residual response to command with EMG in patients with disorders of consciousness (DOC), overcoming the issue of trial dependency and decreasing the influence of a patient's fluctuation of vigilance or arousal over time on diagnostic accuracy. Methods: Forty-five patients with DOC (18 with vegetative/unresponsive wakefulness syndrome [VS/UWS], 22 in a minimally conscious state [MCS], 3 who emerged from MCS [EMCS], and 2 with locked-in syndrome [LIS]) and 20 healthy controls were included in the study. Patients were randomly instructed to either move their left or right hand or listen to a control command ("It is a sunny day") while EMG activity was recorded on both arms. Results: Differential EMG activity was detected in all MCS cases displaying reproducible response to command at bedside on multiple assessments, even though only 6 of the 14 individuals presented a behavioral response to command on the day of the EMG assessment. An EMG response was also detected in all EMCS and LIS patients, and 2 MCS patients showing nonreflexive movements without command following at the bedside. None of the VS/UWS presented a response to command with this method. Conclusions: This method allowed us to reliably distinguish between different levels of consciousness and could potentially help decrease diagnostic errors in patients with motor impairment but presenting residual motor activity. © 2016 American Academy of Neurology

An independent SSVEP-based brain-computer interface in locked-in-syndrome

OBJECTIVE: Steady-state visually evoked potential (SSVEP)-based brain-computer interfaces (BCIs) allow healthy subjects to communicate. However, their dependence on gaze control prevents their use with severely disabled patients. Gaze-independent SSVEP-BCIs have been designed but have shown a drop in accuracy and have not been tested in brain-injured patients. In the present paper, we propose a novel independent SSVEP-BCI based on covert attention with an improved classification rate. We study the influence of feature extraction algorithms and the number of harmonics. Finally, we test online communication on healthy volunteers and patients with locked-in syndrome (LIS). APPROACH: Twenty-four healthy subjects and six LIS patients participated in this study. An independent covert two-class SSVEP paradigm was used with a newly developed portable light emitting diode-based 'interlaced squares' stimulation pattern. MAIN RESULTS: Mean offline and online accuracies on healthy subjects were respectively 85 ± 2% and 74 ± 13%, with eight out of twelve subjects succeeding to communicate efficiently with 80 ± 9% accuracy. Two out of six LIS patients reached an offline accuracy above the chance level, illustrating a response to a command. One out of four LIS patients could communicate online. SIGNIFICANCE: We have demonstrated the feasibility of online communication with a covert SSVEP paradigm that is truly independent of all neuromuscular functions. The potential clinical use of the presented BCI system as a diagnostic (i.e., detecting command-following) and communication tool for severely brain-injured patients will need to be further explored

Preserved Covert Cognition in Noncommunicative Patients With Severe Brain Injury?

Background. Despite recent evidence suggesting that some severely brain-injured patients retain some capacity for topdown processing (covert cognition), the degree of sparing is unknown. Objective. Top-down attentional processing was assessed in patients in minimally conscious (MCS) and vegetative states (VS) using an active event-related potential (ERP) paradigm. Methods. A total of 26 patients were included (38 ± 12 years old, 9 traumatic, 21 patients >1 year postonset): 8 MCS+, 8 MCS−, and 10 VS patients. There were 14 healthy controls (30 ± 8 years old). The ERP paradigm included (1) a passive condition and (2) an active condition, wherein the participant was instructed to voluntarily focus attention on his/her own name. In each condition, the participant’s own name was presented 100 times (ie, 4 blocks of 25 stimuli). Results. In 5 MCS+ patients as well as in 3 MCS− patients and 1 VS patient, an enhanced P3 amplitude was observed in the active versus passive condition. Relative to controls, patients showed a response that was (1) widely distributed over frontoparietal areas and (2) not present in all blocks (3 of 4). In patients with covert cognition, the amplitude of the response was lower in frontocentral electrodes compared with controls but did not differ from that in the MCS+ group. Conclusion. The results indicate that volitional top-down attention is impaired in patients with covert cognition. Further investigation is crucially needed to better understand top-down cognitive functioning in this population because this may help refine brain-computer interface–based communication strategies.Preserved Covert Cognition in Noncommunicative Patients With Severe Brain Injury